JAK-1 Inhibitor Effective for RA, but Safety Signal Troubles

Damian McNamara

November 13, 2017

SAN DIEGO — For patients with active rheumatoid arthritis who respond inadequately to, or cannot tolerate, biologic therapy, the oral selective JAK-1 inhibitor upadacitinib (ABT-494, AbbVie) shows promise, although there are some concerns about a possible safety signal, results from a randomized, double-blind, placebo-controlled, phase 3 study suggest.

"The response rates at week 12 were absolutely phenomenal," said lead investigator Mark Genovese, MD, from the Stanford University Medical Center in Palo Alto, California. "The delta between placebo and active response is probably as good as we've ever seen in a biologics inadequate-responder study."

However, he reported, there was a possible safety signal. There were two venous thrombotic events — pulmonary embolism or deep vein thrombosis — in the first 12 weeks of the trial: one at the 30 mg dose and one at the 15 mg dose. And another four such events occurred from weeks 12 to 24, bringing the total to six.

Even though all affected patients had risk factors for pulmonary embolism or deep vein thrombosis, "we're monitoring venous thrombotic events in the other upadacitinib trials," Dr Genovese told Medscape Medical News.

During the first 12 weeks of the study, 165 patients received once-daily upadacitinib 30 mg, 164 received once-daily upadacitinib 15 mg, and 169 received placebo. During the second 12 weeks, 84 patients in the placebo group were switched to upadacitinib 30 mg and the other 85 were switched to upadacitinib 15 mg.

Dr Genovese presented data on the 91% of participants who completed the first 12 weeks and the 84% who completed the second 12 weeks here at a late-breaking poster session at the American College of Rheumatology 2017 Annual Meeting.

In the study cohort, the mean duration of rheumatoid arthritis was 13 years, mean disease activity score in 28 joints using C-reactive protein (DAS28-CRP) was 5.8, total joint count was 28, swollen joint count was 16.8, and 53% of the patients had a history with at least two biologic disease-modifying antirheumatic drugs (DMARDs).

Significantly more patients in the upadacitinib groups than in the placebo group achieved a 20% improvement in disease activity (ACR20). The same pattern was seen for the secondary end point of disease activity score in 28 joints using C-reactive protein (DAS28-CRP).

Table 1. 12-Week Outcomes in the Three Treatment Groups

Outcome Upadacitinib 30 mg, % (n = 165) Upadacitinib 15 mg, % (n = 164) Placebo, % (n = 169) P Value
ACR20 56 65 28 <.001
DAS28-CRP score ≤3.2 42 43 14 <.001


At 12 weeks, scores on the Health Assessment Questionnaire Without Disability Index (HAQ-DI), indicating quality of life, were significantly better in the upadacitinib groups than in the placebo group.

Table 2. Least Squares Mean Change From Baseline to 12 Weeks

Outcome Upadacitinib 30 mg, % Upadacitinib 15 mg, % Placebo, % P Value
HAQ-DI –0.42 –0.39 –0.17 <.001


At 24 weeks, responses in patients originally assigned to upadacitinib were comparable to responses in those who switched to upadacitinib at 12 weeks.

During the first 12 weeks of the study, the overall frequency of adverse events was comparable in the 15 mg and placebo groups, but was higher in the 30 mg group.

"Everything looked fairly consistent," said Dr Genovese. "We saw occasional adverse events, serious infections, but everything was pretty much straightforward."

The rate of infection was similar in the three treatment groups, but there were more serious infections and cases of herpes zoster in the 30 mg group than in either the 15 mg group or the placebo group. And there were more discontinuations related to adverse events in the 30 mg group than in the other two groups.

The placebo-adjusted response rate was a surprise, Dr Genovese told Medscape Medical News. "I've never seen a response rate in the 60% range in this population."

"This study is very promising. They looked at nearly 500 patients over 6 months to determine the effectiveness of upadacitinib, and the results look pretty convincing," said Bharat Kumar, MD, from the University of Iowa Hospitals and Clinics in Iowa City.

"I am looking forward to more studies on upadacitinib to better determine its long-term effects and safety, but from what the authors have presented, it looks like it has a favorable benefit-to-risk ratio," Dr Kumar told Medscape Medical News.

"There is a growing population that has an inadequate response to our existing therapeutic agents," said Dr Genovese. "Ideally, if you give them a different mechanism of action, particularly this one, you get a surprisingly good response."

Interestingly, he pointed out, in a separate study of upadacitinib presented at the meeting (abstract 1904), there were no cases of pulmonary embolism or deep vein thrombosis in 661 study participants with long-standing, severe, and refractory disease who had an inadequate response to conventional DMARDs.

The study was sponsored by AbbVie. Dr Genovese is an investigator and consultant for AbbVie, Lilly, Pfizer, Galapagos, and Gilead. Dr Kumar has disclosed no relevant financial relationships.

American College of Rheumatology (ACR) 2017 Annual Meeting: Abstract 10L. Presented November 7, 2017.

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